Piperazinocyclohexyl esters



United States Patent PIPERAZINOCYCLOHEXYL ESTERS Seymour L. Shapiro,Hastings on Hudson, Louis Freedman, Bronxville, and Harold Soloway,Yonkers, N.Y.,

assignors to US. Vitamin & Pharmaceutical Corporation, a corporation ofDelaware No Drawing. Filed Nov. 26, 1958, Ser. No. 776,425

6 Claims. (Cl. 260-268) Patented Sept. 27,1960

sides, di basic salts such as the dihydrochloride may be obtained. p

This invention will be more fully described from the examples whichfollow. These examples are set forth by way of illustration only, and itwill be understood that the inventionv is'not to be construed as limitedin spirit or in scope by the details contained therein, since manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in the art.

EXAMPLE 1 I 2-(] [4-methyll piperaz'ino) cyclohexanol A mixture of 50 g.(0.5 mole) of N-methylpiperazine and 44.5 g. (0.25 mole) of cyclohexeneoxide was heated under reflux for 2.3 hours. The excessN-methylpiperazine was removed and the residue of product was dissolvedin heptene. A small quantity of insoluble material such substituentsinclude mono-, d-i-, and trimethoxy, I

lower alkyl, halogen, uitro and amino substituents on the phenyl ring.

The novel compounds of the present invention are thus2-(1-[4methyllpipera2ino)cyclohexyl esters, and

particularly those esters of the benzoic and substituted benzoic acidesters.

The compounds of this invention are depressants of the central nervoussystem and are also potent hypotensive agents. Such properties providein a simple molecule separated. After removing the solvent, the productwas distilled, yielding 40.0 g.' (82%) boiling at 129-13l C. at 4 mm.

The dipic'rate melted at 226-228 C. (methyl ethyl ketone).

Analysis.-Calcd. for C I-I N O C, 42.1; H, 4.3; N, 17.1. Found:' C.42.1; H, 4.2; N, 17.2.

EXAMPLE 2 2- (1-[4 methyllpiperazin0) cyclohexyl benzoate A solution of8.0 g. (0.04 mole) of 2-(1-[4-methyllpiperazino)cyclo-hex-anol in 40 ofacetonitrile was added slowly to 5.6 g. (0.04 mole) of benzoyl chloridein 35 ml. of acetonitrile. A vigorous exothermic reaction occurred withprecipitation of a white sol-id. After standing' overnight, the solventwas removed under vacuum and the residual solid rinsed with ether andfiltered, yielding 12.0 -g. This was taken up in a minimum of water,made basic with continued cooling with 40% aqueous sodium hydroxide andthe free base extracted with five 10-ml. portions of ether. The extractswere combined, dried (anhydrous magnesium sulfate) and filtered. Afterremoval of the solvent and a small forerun, the product distilled at l68172 C. at 0.11 mm., yielding 9.0 g. (75%). 3

Analysis.-Calcd. for C H N O C, 71.5; H, 8.7; N, 9.3 Found: C, 71.7; H,8.8; N, 8.8.

' In a similar manner, using m-bromobenzoyl chloride N-methyldiethylaminoethylamino and N-methyl-dialcohol N N-C HI Reaction with thebenzoyl chloride gives the trans ester of the amino alcohol.

The resultant esters are organic bases and form nontoxic salts with avariety of inorganic acids including hydrochloric, hydrobro-mic andsulfuric acids, as well as with the strong organic acids. Since themolecule has two basic there is obtained2-(1-[4-methyl]piperazino)cyclohexyl m-bromobenzoate; usingp-chlorobenzoyl chloride there is obtained 2-(1-[4-methyllpiperazino)cyclohexyl pchlorobenzoate; and with p-tolylchloride there is obtained 2-(1-[4-methyllpiperazino)cyclohexylp-toluate.

. EXAMPLE 3 2 (1 [4 methyl] piperazino) cyclohexyl 0 methoxybenzaate Asolution of 8.0 g. (0.04 mole) of2-(1-[4-meth-yllpiperazi-no)cyclohexanol in 40 ml. of acetonitrile wasslowly added to 6.8 g. (0.04 mole) of o-methoxyben'zoyl chloride in 35ml. of acetonitrile. A vigorous exothermic reaction ensued withprecipitation of a white solid. After standing overnight, the solventwas removed at diminished pressure and the residue titurated with hexaneto give 14.0 g. of solid. This was converted to the free base in thesame manner as described in Example 2, and distilled to yield 9.3 g.(70%) boiling at -492 C. at 0.1 mm.

Analysis.--Oalcd. for C I-1 N 0 C. 68.6; H, 8.5; N, 8.4. Found: C, 68.9;H, 8.0; N, 8.1.

In a similar manner, using p-methoxybenzoyl chloride there is obtained2-(1-[4-methy1lpiperazino)cyclohexyl p-methoxybenzoate, and withp-ethoxy benzoyl chloride 3 there is obtained2-(1-[4-methyllpiperazino)cyclohexyl p-ethoxybenzoate.

EXAMPLE 4 2 (I [4 methyllpiperazino)cyclohexyl 3,4,5 tfimethoxybenzoatedihydroch loride To a solution of 6.9 g. (0.03 mole) of3,4,5-trirnethoxybenzoyl chloride in 60 ml. of acetonitrile was slowlyadded a solution of 6.0 g. (0.03 mole) of 2-(1-[4-meth- 1y-l]piperazino)cyc-lohexanol in 40 ml. of acetonitrile. An exothermicreaction occurred with formation of a white precipitate. The reactionmixture was .heated underrefiux with stirring for 7 hours. When cool,the solvent was removed at diminished pressure, the residue trituratedwith pentane and the resulting solid (12.5 g.) dissolved in water. Thissolution was made basic with 40% aqueous sodium hydroxide and the freebase extracted with five 20 ml. portions of ether. After drying(magnesium sulfate), the solvent was removed and the oil distilled toremove material boiling below 200 C. at 0.2 mm. The residue wasdis-solved in ether (100* ml.) and hydrogen chloride admitted withcooling. A white precipitate of the dihydrochloride formed. Filtrationyielded 7.0 g. (50%) which was recrystallized (methyl ethylketone-ethanol) to give the product, melting at 220- 223" C.

Analysis-Calcd. for C H Cl 'N O N, 6.0. Found: N, 5.5.

EXAMPLE 5 2 (I [4 methyllpiperazino)cyclohexyl p-nitrobenzoatehydnochloria'e A solution of 10.0 g. (0.05 mole) of2-(1-[4-methyl]piperazino)cyc1ohexanol in 50 ml. of acetonitrile wasslowly added to 9.3 g. (0.05 mole) of p-nitrobenzoyl chloride in 50 ml.of acetonitrile, inducing a vigorous exothermic reaction. After allowingthe reaction mixture to stand 24 hours at room temperature and thenrefrigerating, the solid :was filtered ofi, yielding 10.0 g., M.P.206208 C. An additional 4.0 g. was recovered from the filtrate onevaporation and trituration with ether.

Recrystallization from ethanol gave 8.5 g. (42%) .of themonohydrochloride hemidrate, melting at 216- 218 C.

Analysis.Calcd. for C H ClN O J/2'H O: C, 55.0; H, 6.9; N, 11.0. Found:C, 55.1; H, 7.0; N, 10.8.

EXAMPLE '6 2 (I [4 methyflpiperazinp)cylclohexyl p-aminobenzo'atehydrochloride 2- l- [4-methyl] piperazino cyclohexyl p-nitrobenzoatemonohydrochloridc hemihydrate (7.7 g., 0.02 mole) was dissolved in 250ml. of 75% aqueous ethanol, 0.2 g. of platinum dioxide added and themixture hydrogenated in a Parr hydrogenator at room temperature. After 8hours, the theoretical quantity of hydrogen was consumed. -Filtrationand removal of the solvent gave a brown gum which was triturated withether to yield 6.2 g. (81%). Recrystallization (methyl ethylketone-ethanol) gave 2.5 g. (33%) of the sesquihydrate, decomposing at164 C.

Analysis.Calcd. for C H ClN O .l.5 H O: C, 56.8; H, 8.2; N, 11.0. Found:C, 57.2; H,'8.7; N, 11.0.

v A dipicrate was prepared and recrystallized from a mixture ofmethanol, acetone and water, decomposing at 239-241" C.

Analysis.Ca-lcd. for C 'H N O C, 46.5;H, 4.3; N, 16.3. Found: C, 46.4;H, 4.4; N, 16.0.

It is to be understood that it is intended to cover all changes andmodifications of the examples of the invention herein chosen for thepurpose of illustration which do not constitute departures from thespirit and scope of the invention.

We claim: 1. The cyclohexyl ester of the following formula \N/ NCH3wherein R is a member of the group consisting of hydrogen, methyl,amino, nitro, halogen, methoxy and trimethoxy.

2. The compound- OCHa O etqm...

References Cited in the file of this patent Godchot et al.: ComptesRendus, vol. 194, pp. 616-617 1932) Shriner et al.: Identification ofOrganic Compounds,

pp. 159l60, 3rd ed. (1948).

1. THE CYCLOHEXYL ESTER OF THE FOLOWING FORMULA